研究者詳細 - 加畑　宏樹

論文 - 加畑　宏樹

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The effect of statins for asthma. A systematic review and meta-analysis.

Sunata K, Kabata H, Kuno T, Takagi H, So M, Masaki K, Fukunaga K

The Journal of asthma : official journal of the Association for the Care of Asthma （Journal of Asthma） 59 （ 4 ） 1 - 10 2021年02月

ISSN 0277-0903

Objective: To assess the effects of statins on asthma by systematically reviewing and conducting a meta-analysis on all clinical studies, including randomized controlled trials (RCTs) and observational studies, that examined the effects of statins on asthma. Methods: PubMed, EMBASE databases, and Cochrane reviews were searched to identify RCTs and observational studies, conducted through June 16, 2020, that assessed the effect of statins as a treatment for asthma. A meta-analysis was conducted using the following main outcomes: asthma control test (ACT), asthma control questionnaire (ACQ), pre- and post-bronchodilator forced expiratory volume in one second (FEV1), peak flow (PEF), and asthma exacerbation (asthma-related emergency department (ED) visits and hospitalization). Results: Our search revealed 11 RCTs and 8 observational studies that met the inclusion criteria. A meta-analysis demonstrated that statin treatment significantly improved ACT scores (mean difference: 1.61, P < 0.001) and ACQ scores (mean difference: −0.38, P < 0.001) compared to a placebo. Furthermore, statin treatment significantly reduced asthma-related ED visits (hazard ratio [HR], 95% confidence interval [CI], 0.83 [0.75–0.92], P < 0.001, number needed to treat [NNT], 5.9). However, statin treatment did not improve pulmonary function (FEV1 and PEF). Conclusion: Our results suggest that statins have the potential to improve asthma control and reduce asthma exacerbation without any improvement in pulmonary function. Supplemental data for this article can be accessed at publisher’s website.

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The real-time reverse transcription-polymerase chain reaction threshold cycle values for severe acute respiratory syndrome coronavirus 2 predict the prognosis of coronavirus disease 2019 pneumonia.

Fukushima T, Kabata H, Yamamoto R, Suhara T, Uwamino Y, Kondo Y, Masaki K, Kamata H, Nagata H, Homma K, Kaneko Y, Ishii M, Sasaki J, Morisaki H, Hasegawa N, Fukunaga K, Keio Donner Project Team.

Respiratory investigation （Respiratory Investigation） 59 （ 3 ） 360 - 363 2021年01月

ISSN 2212-5345

The clinical course of coronavirus disease 2019 (COVID-19) varies from mild to critical. We retrospectively examined whether clinical and laboratory findings on admission could predict COVID-19 prognosis. Among various factors associated with COVID-19 severity, our results indicated that the real-time reverse transcription-polymerase chain reaction (RT-PCR) threshold cycle (Ct) values for severe acute respiratory syndrome coronavirus 2 were the most useful predictor of COVID-19 prognosis.

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Left Ventricular Thrombus With COVID-19 Complication in a Patient With Dilated Cardiomyopathy.

Imaeda S, Kabata H, Shiraishi Y, Kamata H, Tsuruta H, Yuasa S, Ishii M, Fukuda K, Fukunaga K

CJC open （CJC Open） 3 （ 1 ） 124 - 126 2021年01月

© 2020 Canadian Cardiovascular Society Thrombosis, especially venous thromboembolism, is a complication often associated with coronavirus disease 2019 (COVID-19). However, there have been relatively few reports of arterial thrombosis. Here, we describe a case of non-severe COVID-19 in a patient with dilated cardiomyopathy. After admission, symptoms, laboratory data, and imaging findings improved, but D-dimer levels gradually increased. Contrast computed tomography and echocardiography revealed a left ventricular thrombus. Anticoagulant treatment diminished the thrombus, and the patient recovered and was discharged. Although a left ventricular thrombus is a rare COVID-19 complication, performing appropriate diagnostic tests could improve COVID-19 mortality in patients with dilated cardiomyopathy.

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Clinical characteristics of patients with not well-controlled severe asthma in Japan: Analysis of the Keio Severe Asthma Research Program in Japanese population (KEIO-SARP) registry.

Tanosaki T, Kabata H, Matsusaka M, Miyata J, Masaki K, Mochimaru T, Okuzumi S, Kuwae M, Watanabe R, Suzuki Y, Sayama K, Izuhara K, Asano K, Fukunaga K

Allergology international : official journal of the Japanese Society of Allergology （Allergology International） 70 （ 1 ） 61 - 67 2021年01月

ISSN 1323-8930

© 2020 Japanese Society of Allergology Background: Multiple phenotypes exist within the classification of severe asthma. However, characteristics of patients with not well-controlled severe asthma have not been well identified. Methods: Japanese patients with asthma (age ≥ 20 years) were enrolled at the Keio University Hospital and its affiliated hospitals in this observational study (Keio Severe Asthma Research Program). Among them, patients with severe asthma (those undergoing Global Initiative for Asthma [GINA] 2018 step 4 or 5 treatment) were included in this analysis and investigated clinical characteristics based on asthma control status. Results: Of the 154 patients (men, 46.8%; age, 60.1 ± 14.9 years), 87 (56.5%) had not well-controlled (partly controlled and uncontrolled) asthma (GINA step 4, 42 patients; step 5, 45 patients). Overall, there were no significant differences in clinical characteristics between patients with well-controlled and not well-controlled asthma. However, cluster analysis revealed that distinct 5 clusters (cluster 1, well-controlled; cluster 2, eosinophilic; cluster 3, non–type 2 inflammation; cluster 4, high periostin; and cluster 5, late-onset type 2 inflammation), and clusters 2–5 were not well-controlled. Among them, cluster 3 was characterized by low eosinophil counts, low periostin levels, and less frequent olfactory disturbance, and this cluster had the worst asthma control. Conclusions: Japanese patients with severe asthma were divided into well-controlled and not-well controlled asthma, and we confirmed heterogeneity of not well-controlled severe asthma. These patients, especially non-type 2 phenotype, require a further therapeutic approach. (University Hospital Medical Information Network Clinical Trials Registry, UMIN000002980)

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Accuracy and stability of saliva as a sample for reverse transcription PCR detection of SARS-CoV-2.

Uwamino Y, Nagata M, Aoki W, Fujimori Y, Nakagawa T, Yokota H, Sakai-Tagawa Y, Iwatsuki-Horimoto K, Shiraki T, Uchida S, Uno S, Kabata H, Ikemura S, Kamata H, Ishii M, Fukunaga K, Kawaoka Y, Hasegawa N, Murata M

Journal of clinical pathology （Journal of Clinical Pathology） 74 （ 1 ） 67 - 68 2021年01月

ISSN 0021-9746

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Clinical characteristics of 345 patients with coronavirus disease 2019 in Japan: A multicenter retrospective study.

Ishii M, Terai H, Kabata H, Masaki K, Chubachi S, Tateno H, Nakamura M, Nishio K, Koh H, Watanabe R, Ueda S, Terashima T, Suzuki Y, Yagi K, Miyao N, Minematsu N, Inoue T, Nakachi I, Namkoong H, Okamori S, Ikemura S, Kamata H, Yasuda H, Kawada I, Hasegawa N, Fukunaga K, Keio COVID-19 Research Consortium (K-CORC) and the Keio Donner Project Team.

The Journal of infection （Journal of Infection） 81 （ 5 ） e3 - e5 2020年11月

ISSN 0163-4453

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Effectiveness of Face Masks in Preventing Airborne Transmission of SARS-CoV-2.

Ueki H, Furusawa Y, Iwatsuki-Horimoto K, Imai M, Kabata H, Nishimura H, Kawaoka Y

mSphere （mSphere） 5 （ 5 ） 2020年10月

ISSN 2379-5042

Copyright © 2020 Ueki et al. Guidelines from the CDC and the WHO recommend the wearing of face masks to prevent the spread of coronavirus (CoV) disease 2019 (COVID-19); however, the protective efficiency of such masks against airborne transmission of infectious severe acute respiratory syndrome CoV-2 (SARS-CoV-2) droplets/aerosols is unknown. Here, we developed an airborne transmission simulator of infectious SARS-CoV-2-containing droplets/aerosols produced by human respiration and coughs and assessed the transmissibility of the infectious droplets/aerosols and the ability of various types of face masks to block the transmission. We found that cotton masks, surgical masks, and N95 masks all have a protective effect with respect to the transmission of infective droplets/aerosols of SARS-CoV-2 and that the protective efficiency was higher when masks were worn by a virus spreader. Importantly, medical masks (surgical masks and even N95 masks) were not able to completely block the transmission of virus droplets/aerosols even when completely sealed. Our data will help medical workers understand the proper use and performance of masks and determine whether they need additional equipment to protect themselves from infected patients.IMPORTANCE Airborne simulation experiments showed that cotton masks, surgical masks, and N95 masks provide some protection from the transmission of infective SARS-CoV-2 droplets/aerosols; however, medical masks (surgical masks and even N95 masks) could not completely block the transmission of virus droplets/aerosols even when sealed.

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Acute onset olfactory/taste disorders are associated with a high viral burden in mild or asymptomatic SARS-CoV-2 infections.

Nakagawara K, Masaki K, Uwamino Y, Kabata H, Uchida S, Uno S, Asakura T, Funakoshi T, Kanzaki S, Ishii M, Hasegawa N, Fukunaga K, Keio Donner Project.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases （International Journal of Infectious Diseases） 99 19 - 22 2020年10月

ISSN 1201-9712

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A case of non-severe COVID-19 complicated by pulmonary embolism.

Akiyama Y, Horiuchi K, Kondo Y, Kabata H, Ishii M, Fukunaga K

Respirology case reports （Respirology Case Reports） 8 （ 7 ） e00622 2020年10月

ISSN 2051-3380

© 2020 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology. Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is rapidly spreading worldwide. A typical clinical manifestation of COVID-19 is pneumonia, which can progress to acute respiratory distress syndrome and respiratory failure. Recent studies have reported that COVID-19 is often accompanied by coagulopathy, and a significant number of patients with severe or critical COVID-19 develop concomitant thrombosis, including pulmonary embolism (PE). However, there are limited reports of the incidence of PE in non-severe COVID-19 patients. Here, we report a case of non-severe COVID-19 complicated by PE, which indicates that the possibility of PE should consistently be considered, even in non-severe cases of COVID-19 without any risk of thrombosis.

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Coronavirus disease 2019-associated rapidly progressive organizing pneumonia with fibrotic feature: Two case reports.

Okamori S, Lee H, Kondo Y, Akiyama Y, Kabata H, Kaneko Y, Ishii M, Hasegawa N, Fukunaga K

Medicine （Medicine） 99 （ 35 ） e21804 2020年08月

ISSN 0025-7974

INTRODUCTION: Pneumonia is one of the most important characteristics of coronavirus disease 2019 (COVID-19) and imaging findings of COVID-19 pneumonia are diverse and change over disease course. However, the detailed clinical course of organizing pneumonia (OP) caused by COVID-19 has not been clarified. PATIENT CONCERNS: A 60-year-old man and a 61-year-old woman diagnosed with mild COVID-19 were admitted to our hospital. Their respiratory symptoms were deteriorating even after initiating treatment with antiviral drugs. DIAGNOSIS: Chest X-rays and computed tomography scan showed a rapid progression of linear consolidation with reversed halo sign, distributed in subpleural and peri-bronchial regions. They also presented with pulmonary fibrosis findings, including traction bronchiectasis and marked lung volume reduction. They were diagnosed with rapidly progressing OP. INTERVENTIONS: They were treated with systemic corticosteroids. OUTCOMES: The patients' imaging findings and respiratory conditions improved rapidly without any adverse effects. CONCLUSION: Physicians should carefully monitor patients with COVID-19, as they can develop rapidly progressive and fibrotic OP, which respond to corticosteroids.

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Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation.

Kabata H, Flamar AL, Mahlakõiv T, Moriyama S, Rodewald HR, Ziegler SF, Artis D

Mucosal immunology （Mucosal Immunology） 13 （ 4 ） 626 - 636 2020年07月

ISSN 1933-0219

© 2020, The Author(s). Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.

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Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma.

Masaki K, Miyata J, Kamatani T, Tanosaki T, Mochimaru T, Kabata H, Suzuki Y, Asano K, Betsuyaku T, Fukunaga K

Asian Pacific journal of allergy and immunology 2020年06月

ISSN 0125-877X

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Anti-TSLP antibodies: Targeting a master regulator of type 2 immune responses.

Nakajima S, Kabata H, Kabashima K, Asano K

Allergology international : official journal of the Japanese Society of Allergology （Allergology International） 69 （ 2 ） 197 - 203 2020年04月

ISSN 1323-8930

© 2020 Japanese Society of Allergology TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined.

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Distinct TSLP-Immune Cell Cascades Provoke Acute Versus Chronic Type 2 Airway Inflammation

Kabata H., Artis D.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 201 2020年

ISSN 1073-449X

Neuro-immune crosstalk and allergic inflammation

Kabata H., Artis D.

Journal of Clinical Investigation （Journal of Clinical Investigation） 129 （ 4 ） 1475 - 1482 2019年04月

査読有り, ISSN 00219738

© 2019 American Society for Clinical Investigation. The neuronal and immune systems exhibit bidirectional interactions that play a critical role in tissue homeostasis, infection, and inflammation. Neuron-derived neuropeptides and neurotransmitters regulate immune cell functions, whereas inflammatory mediators produced by immune cells enhance neuronal activation. In recent years, accumulating evidence suggests that peripheral neurons and immune cells are colocalized and affect each other in local tissues. A variety of cytokines, inflammatory mediators, neuropeptides, and neurotransmitters appear to facilitate this crosstalk and positive-feedback loops between multiple types of immune cells and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems. In this Review, we discuss these recent findings regarding neuro-immune crosstalk that are uncovering molecular mechanisms that regulate inflammation. Finally, neuro-immune crosstalk has a key role in the pathophysiology of allergic diseases, and we present evidence indicating that neuro-immune interactions regulate asthma pathophysiology through both direct and indirect mechanisms.

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Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2.

Zhou L, Chu C, Teng F, Bessman NJ, Goc J, Santosa EK, Putzel GG, Kabata H, Kelsen JR, Baldassano RN, Shah MA, Sockolow RE, Vivier E, Eberl G, Smith KA, Sonnenberg GF

Nature （Nature） 568 （ 7752 ） 405 - 409 2019年04月

ISSN 0028-0836

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract 1–4 . The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (T reg ) cells 4–8 , and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease 9 . However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1β. Macrophages in the small intestine produce IL-1β, and activation of this pathway involves MYD88- and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining T reg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn’s disease, and this correlated with lower frequencies of T reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.

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Influence of the Number Multiple Disease-Modifying Factors in Japanese Patients with Severe Asthma

Watanabe R., Baba R., Kamatani T., Kuwae M., Okuzumi S., Tanosaki T., Matsusaka M., Mochimaru T., Kabata H., Ueda S., Suzuki Y., Asano K., Fukunaga K.

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 199 2019年

ISSN 1073-449X

Response to Fungal Dysbiosis by Gut-Resident CX3CR1 <sup>+</sup> Mononuclear Phagocytes Aggravates Allergic Airway Disease

Li X., Leonardi I., Semon A., Doron I., Gao I., Putzel G., Kim Y., Kabata H., Artis D., Fiers W., Ramer-Tait A., Iliev I.

Cell Host and Microbe （Cell Host and Microbe） 24 （ 6 ） 847 - 856.e4 2018年12月

ISSN 19313128

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The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

Kabata H., Moro K., Koyasu S.

Immunological Reviews （Immunological Reviews） 286 （ 1 ） 37 - 52 2018年11月

ISSN 01052896

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-β), transdifferentiation cytokines (IL-12; STAT4, IL-1β, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+-NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+-NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2-related health problems.

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12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs

Mochimaru T., Fukunaga K., Miyata J., Matsusaka M., Masaki K., Kabata H., Ueda S., Suzuki Y., Goto T., Urabe D., Inoue M., Isobe Y., Arita M., Betsuyaku T.

Allergy: European Journal of Allergy and Clinical Immunology （Allergy: European Journal of Allergy and Clinical Immunology） 73 （ 2 ） 369 - 378 2018年02月

ISSN 01054538

© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd. Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

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